11-66756337-CT-C

Variant names:

• chr11-66756337-CT-C
• rs538618909
• NM_001302084.2:c.-29-2696delT

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_024650.4(TOP6BL):​c.170-6delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0152 in 1,081,708 control chromosomes in the GnomAD database, including 84 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.011 (12 hom., cov: 31)
  • Exomes 𝑓: 0.016 (72 hom.)
• Consequence: TOP6BL NM_024650.4 splice_region, intron
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.538

Genes affected

TOP6BL (HGNC:26197): (TOP6B like initiator of meiotic double strand breaks) Predicted to be involved in meiotic DNA double-strand break formation and reciprocal meiotic recombination. Predicted to be located in chromosome. Implicated in gestational trophoblastic neoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP6: Variant 11-66756337-CT-C is Benign according to our data. Variant chr11-66756337-CT-C is described in ClinVar as [Likely_benign]. Clinvar id is 3055765.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0111 (1659/149214) while in subpopulation NFE AF= 0.0159 (1066/67076). AF 95% confidence interval is 0.0151. There are 12 homozygotes in gnomad4. There are 760 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOP6BL	NM_001302084.2	c.-29-2696delT		intron_variant	Intron 1 of 14	ENST00000540737.7	NP_001289013.1
TOP6BL	NM_024650.4	c.170-6delT		splice_region_variant, intron_variant	Intron 2 of 16		NP_078926.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C11orf80	ENST00000540737.7	c.-29-2705delT		intron_variant	Intron 1 of 14	2	NM_001302084.2	ENSP00000444319.1
C11orf80	ENST00000525449.6	c.-149-15delT		intron_variant	Intron 1 of 14	1		ENSP00000434648.2

Frequencies

GnomAD3 genomes AF: 0.0111 AC: 1659 AN: 149118 Hom.: 12 Cov.: 31

Gnomad AFR AF: 0.00546

Gnomad AMI AF: 0.0298

Gnomad AMR AF: 0.0153

Gnomad ASJ AF: 0.0134

Gnomad EAS AF: 0.000391

Gnomad SAS AF: 0.00470

Gnomad FIN AF: 0.00130

Gnomad MID AF: 0.0128

Gnomad NFE AF: 0.0159

Gnomad OTH AF: 0.0148

GnomAD3 exomes AF: 0.0411 AC: 1044 AN: 25382 Hom.: 6 AF XY: 0.0407 AC XY: 566 AN XY: 13902

Gnomad AFR exome AF: 0.0300

Gnomad AMR exome AF: 0.0426

Gnomad ASJ exome AF: 0.0536

Gnomad EAS exome AF: 0.0153

Gnomad SAS exome AF: 0.0332

Gnomad FIN exome AF: 0.0309

Gnomad NFE exome AF: 0.0483

Gnomad OTH exome AF: 0.0430

GnomAD4 exome AF: 0.0158 AC: 14737 AN: 932494 Hom.: 72 Cov.: 24 AF XY: 0.0158 AC XY: 7123 AN XY: 450934

Gnomad4 AFR exome AF: 0.00721

Gnomad4 AMR exome AF: 0.0198

Gnomad4 ASJ exome AF: 0.0197

Gnomad4 EAS exome AF: 0.00538

Gnomad4 SAS exome AF: 0.00995

Gnomad4 FIN exome AF: 0.00878

Gnomad4 NFE exome AF: 0.0164

Gnomad4 OTH exome AF: 0.0163

GnomAD4 genome AF: 0.0111 AC: 1659 AN: 149214 Hom.: 12 Cov.: 31 AF XY: 0.0104 AC XY: 760 AN XY: 72734

Gnomad4 AFR AF: 0.00544

Gnomad4 AMR AF: 0.0153

Gnomad4 ASJ AF: 0.0134

Gnomad4 EAS AF: 0.000392

Gnomad4 SAS AF: 0.00470

Gnomad4 FIN AF: 0.00130

Gnomad4 NFE AF: 0.0159

Gnomad4 OTH AF: 0.0147

Bravo AF: 0.0125

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

TOP6BL-related disorder Benign:1

Feb 22, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs538618909; hg19: chr11-66523808;